Long-term follow up of Myeloma X: a phase III trial investigating the impact of cytogenetics in patients with relapsed multiple myeloma

Myeloma X Relapse (Intensive) trial (ISCRTN60123120 and NCT00747877) is the first randomized, phase III study investigating salvage autologous stem cell transplant (ASCT) at first relapse in patients with multiple myeloma (MM). The full details of the trial, including its closure, have previously been published by Cook et al. which showed the depth of response to salvage ASCT confers a survival advantage.^1,2 Subsequently, this report from Gordon Cook, University of Leeds, United Kingdom, and colleagues provides an updated analysis on time to progression (TTP), progression free survival (PFS), second progression free survival (PFS2) and overall survival (OS) with a median follow-up of 76 months.

Significantly, investigators obtained chromosomal analysis of all patients at registration (baseline, first relapse) in order to assess the effect of specific cytogenetic abnormalities on TTP, PFS, PFS2 and OS. They also analyzed the effect of subclonal selection and post-trial ASCT on OS.³

Study Design

• Multicenter, randomized, open-label, phase III trial in the United Kingdom
• Eligibility: symptomatic, measurable MM requiring treatment for first progressive disease, at least 18 months following ASCT
• In total, 297 patients were registered, with an intention to treat (ITT) population of 174 patients
  • Randomized to either salvage ASCT (N = 89) or weekly cyclophosphamide (N = 85) following re-induction therapy
  • Twenty one patients randomized to weekly cyclophosphamide subsequently had an ASCT post-trial
• Baseline cytogenetic analysis looked at the presence of: t(4;14), t(11;14), del(17p), 13q deletion, hyperdiploidy and MYC rearrangement
• Adverse risk cytogenetics: presence of ≥1 of; t(4;14), t(14;16) or del(17p)
• In the ITT population (N = 174):
  • Eighty eight patients had cytogenetic analysis (43 in ASCT group vs 45 in cyclophosphamide group)
  • Thirteen patients had adverse risk cytogenetics

Key Findings

All findings are reported as salvage ASCT versus cyclophosphamide in the ITT population (N = 174) unless otherwise stated:

• TTP: 19 months (95% CI, 16–26) vs 11 (95% CI, 9–12) Disease progressions: 77 (86.5%) vs 81 (95.3%)
  • Hazard ratio (HR): 0.40 (95% CI, 0.29–0.56, P < 0.001)
• PFS: total events: 160 (92.0%)
  • PFS events: 79 (88.8%) vs 81 (95.3%)
  • Median PFS: 19 months (95% CI, 16–25) vs 11 (95% CI, 9–12)
  • HR: 0.41, 95% CI: 0.30–0.58, P < 0.001
• PFS2: total events: 112 (64.4%)
  • Progressions or deaths: 47 (52.8%) vs 65 (76.5%)
  • Median PFS2: 62 months (95% CI, 47–72) vs 35 (95% CI, 31–46)
  • HR: 0.45, 95% CI: 0.3–0.66, P < 0.001
  • Of 21 patients receiving ASCT post-trial vs those who did not receive ASCT post-trial: 31 months (95% CI, 24–43) vs 38 (95% CI, 32–48) months
• OS: 67 months (95% CI, 59–not reached [NR]) vs 55 (95% CI 44–67)
  • HR: 0.64 (95% CI, 0.42–0.99, P = 0.0435)
  • In total, 90 deaths occurred: 44.9% (n = 40) vs 58.5% (n = 50)
  • Disease progression responsible for 63.3% of deaths
  • Estimated median OS accounting for patients receiving ASCT post trial in cyclophosphamide group: 52 months (95% CI, 41–NR) - median improvement of 3 months in OS and slight reduction in HR when adjusted
  • Median OS (ASCT post-trial vs no ASCT): NR (95% CI, 39–NR) vs 31 months (22–39)

Cytogenetic Analysis

• Forty one patients had cytogenetic analysis at diagnosis and at first relapse:
  • Eleven patients with hyperdiploidy at diagnosis no longer tested positive at first relapse. Two patients gained the feature
  • Four patients had del(13q) at diagnosis but not first relapse. One patient gained the feature
  • Five patients evolved to high-risk at first relapse
  • Two patients devolved to standard risk
  • Four patients retained high-risk cytogenetics
• No evidence that link genetic abnormalities with depth of response
• Significant evidence in patients with MYC rearrangement that treatment is heterogeneous and has a deleterious impact

The long-term follow-up of Myeloma X confirmed salvage ASCT improved TTP, PFS and OS. The benefit of post-trial ASCT in the cyclophosphamide group was shown through adjusted OS, which was improved, suggesting that a second, salvage ASCT may have a role in later therapy lines, after first relapse.

This study is the first in the ASCT setting to identify that changes in the clonal genetic landscape can occur in MM between diagnosis and relapse. Additionally, the presence of adverse cytogenetics at relapse can reduce the efficacy of second-line therapy. Whilst the presence of t(4;14), t(14;16) or del(17p) alone did not prevent a PFS or OS advantage in salvage ASCT over cyclophosphamide, the presence of MYC rearrangement had a deleterious impact. Understanding the mechanisms of MYC deregulation fully may provide new approaches for treatment. This analysis also highlights the requirement for trials in this specific sub-group.